NIH Awards Aim to Improve Understanding of Cell Pathways, Development of New Therapies

Building on a successful 3-year pilot project, the National Institutes of Health (NIH) has awarded more than $64 million to six individuals at five research institutions to create a database of human cellular responses—the Library of Integrated Network-based Cellular Signatures (LINCS). Discovering such cell responses will improve scientists’ understanding of cell pathways and aid in the development of new therapies for many diseases. LINCS data will be freely available to any scientist.

The funding establishes six centers, collectively called the Data and Signature Generating Centers. The National Human Genome Research Institute ­(NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) administer the program.

The LINCS program aims to catalog and analyze cellular function and molecular activity in response to perturbing agents such as drugs and genetic factors. LINCS researchers then will measure the cells’ molecular and biochemical responses and use computer analyses to uncover “signatures.”

“The simplest way to think about signatures is as broad common patterns, as well as uncommon behavior, in how cells respond to various small molecules or genetic changes,” said Ajay Pillai, PhD, Program Director in NHGRI’s Division of Genome Sciences, and Co-Coordinator of the LINCS program, along with Albert Lee, PhD, Program Director in NHLBI’s Division of Cardiovascular ­Sciences.

The OHSU team will study how both malignant and nonmalignant cells are controlled by the microenvironments in which they live. The researchers will provide measurements of the impacts of thousands of different microenvironments on cellular phenotypes, protein makeup, and gene-expression readouts in cell lines.

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge

$12.56 million over 6 years—Principal Investigator: Todd Golub, MD

The Golub team will study up to 50 cell types perturbed by a large number of chemical compounds and genetic reagents. Each perturbation will produce about 1,000 gene-expression readouts. By the project’s end, Dr. Golub expects to have generated more than 1 million profiles of how genes are expressed in different cells.

$8.9 million over 6 years—Principal Investigator: Jacob D. Jaffe, PhD

Dr. Jaffe’s LINCS Center for Proteomic Characterization of Signaling and Epigenetics will study cell disruption at the most basic levels: phosphorylation-mediated signaling and epigenetics. These latter signals are transmitted in part by modifications to histone proteins, around which the DNA in cells is wrapped.

Icahn School of Medicine at Mount Sinai, New York City, $11.39 million over 6 years—Principal Investigator: Srinivas (Ravi) Iyengar, PhD

Dr. Iyengar’s Drug Toxicity Signature Center aims to develop cell signatures that will predict adverse events that might be caused by drugs and will identify other drugs that might lessen these side effects. The researchers will leverage the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System database to identify drugs that produce adverse events in heart, liver, and neuronal function and to search for drugs that may mitigate these events.

The Thompson team will concentrate on human brain cells. By applying LINCS-type perturbations to studying an array of human brain cells, the researchers hope to identify targets for developing drugs against neurodegenerative diseases such as Parkinson’s disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington’s disease. The National Institute of Neurological Disorders and Stroke (NINDS) is funding Dr. Thompson’s grant. ■